Metabolic uncoupling therapy

ABSTRACT

A combination of chemical agents reduces reductive stress by limiting the accumulation of high-energy electrons potentially available to the electron transport chain. A method of metabolic uncoupling therapy comprises: analyzing a specific physiologic process involving reductive stress; identifying a plurality of MUT agents that modulate metabolic pathways by influencing electron flux; and formulating a combination of MUT agents that limits the accumulation of high-energy electrons potentially available to the electron transport chain.

FIELD OF THE INVENTION

[0001] This invention relates in general to novel concepts involving themetabolism of high-energy electrons in animals, and more particularly totheir physiological effects in mammals.

BACKGROUND OF THE INVENTION

[0002] There is currently an epidemic of lifestyle related healthdisorders. These include, but are not limited to, high blood pressure,diabetes, dyslipidemia, hyperlipidemia, hypercholesterolemia, insulinresistance, inflammation, vascular disease, heart disease, stroke,overweight, obesity, neuronal and/or cognitive dysfunction, dementia,attention and attention/hyperactivity disorders, mood disorders,muscular damage, muscular deterioration or soreness, athleticcompromise, sarcopenia, glucose intolerance and other disorders ofglucose metabolism, premature aging, skin deterioration and/or damageeither associated with, or not associated with, sun exposure, loss ofmuscle tone, frailty, and bone loss.

[0003] Many of these disorders may be understood by analysis of theforces that shaped the evolution of mankind. This analysis providesinsight into the interactions between the current environment and thehuman genome.

[0004] Genetic adaptations proceed on a scale measured in hundreds ofthousands of years. In contrast, current environmental and dietarychanges occur in a much-accelerated fashion. Our “stone age” genes are apoor match for the demands placed upon them by our current lifestyles.This dys-synchrony is manifestly responsible for the predisposition to,and development of, chronic disease.

[0005] Multiple factors form the mechanistic basis for the adversebiological processes responsible for the development of chronic diseaseand many other health problems. An understanding of these factors isimportant in the fashioning of a meaningful treatment approach. Themultiple biological processes, and the resulting forces exerted by themin an organism, have evolved over millions of years and form the basisfor the current intricate biological actions and reactions that occur atthe cellular level. Each metabolic pathway consists of many small,carefully orchestrated steps that modulate, and in turn are influencedby, many of the chemical pathways within each cell. The most fundamentalcellular processes are involved. Subtle effects are magnified many foldat each step of every pathway until ripples are felt in the far reachesof the cell. A perturbation in a metabolic pathway that produces changesexceeding the normal ranges developed through evolution forces mayultimately derail the delicate chemical balance that forms the basis forcellular homeostasis. When this happens, cells, tissues, organs, andeven organisms manifest various disease processes.

[0006] The evolutionary history responsible for the current metabolicprocesses in organisms tells an interesting story. The most fundamentalproperty of all living organisms involves the ability to extract andharness energy from their surroundings. This energy is used to drivethermodynamically unfavorable processes involving the generation ofcellular order and complexity. They form the basis for cellularfunctions. These include growth, repair, and reproduction.

[0007] In the evolutionary development of living organisms, apparentlythe safest and most efficient mechanism for cellular energy transductioninvolved the directed flow of high-energy electrons down an energyladder in multiple small steps. Each downward step involved the transferof an electron from one state to another, slightly lower in energy. Thiswas associated with the release of a packet of energy in a biologicallyacceptable manner, which could be captured and saved for future use.These processes were present in the earliest formulations ofphotosynthesis and metabolism. They constituted the earliest design ofan electron transport chain (ETC). These processes were in place beforeoxygenic photosynthesis evolved, thus predating the oxidizing atmospherethat dominates the earth today.

[0008] Weak electron acceptors such as hydrogen sulfide, organic acids,and nitrate were initially utilized. This only allowed generation ofmeager amounts of energy. Nevertheless, when atmospheric oxygen becameavailable in high concentration, it became the preferred electronacceptor because it allowed for much more energy generation from fuelsources and had very distinct survival value. Life's transition to anoxygen-rich atmosphere two billion years ago allowed for theunprecedented generation of cellular energy. This benefit wasaccompanied by the problems of coping with the corrosive and reactiveoxygen molecule. The evolutionary events over the past two billion yearsprovided for the development of a modern compromise between the need fora highly efficient oxidative phophorylation process and the need tosafely handle the damaging and aging effects of reactive oxygen species(ROS).

[0009] The ETC resides on the inner mitochondrial membrane. High-energyelectrons flow down an energy gradient while protons are pumped acrossthe mitochondrial membrane. Adenosine triphosphate (ATP) is generated asthe protons are transported back across the mitochondrial membrane intothe mitochondrial matrix region. For maximal energy (i.e., ATP)production, efficient coupling must exist between the reentry of theprotons and ATP generation. In recent years, it has been demonstratedthat a finite cellular-membrane proton-conductance exists that is notcoupled with ATP generation. This process has been observed to dissipate20% to 25% of the basal metabolic rate. This is a surprisingly highlevel of ETC inefficiency that has been preserved over the eons. Becauseof its high metabolic cost, it must logically provide an extraordinarybenefit for the survival of the cell.

[0010] Cells have developed powerful anti-oxidant defenses to protectthemselves against damage from reactive oxygen species, ROS, whichtypically comprise free oxygen radicals. Attention in the field has beendevoted exclusively to these anti-oxidants. Their function is to springinto action after a free radical is generated and to inactivate orquench it. Even though prevention rather than cure is a more logical wayto decrease oxidative damage, no attention has been paid to processesthat are critical in the production or generation of ROS. Evidence thatforces regulating ROS-production, rather than ex post facto quenching offree radicals, are important and are related to the production ofdisease; and aging includes the observation that ROS-production ishigher in mitochondria from animals with shorter maximal lifespan.

SUMMARY OF THE INVENTION

[0011] Metabolic uncoupling therapy (MUT) in accordance with the presentinvention treat the conditions discussed above by providing methods andcompositions that limits the accumulation of high-energy electronspotentially available to the electron transport chain.

[0012] Various treatments in accordance with the present inventionprovide enhanced health benefits also by utilizing numerous synergisticmechanisms that together tend to reduce generation of ROS, reduce thePMF, and improve cellular redox status, based upon novel techniquesdescribed herein.

[0013] Analysis of the mechanistic development of chronic diseases andhealth disorders, in accordance with the invention, enables theappropriate selection of MUT agents to make novel therapeuticformulations.

[0014] Formulations of various combinations of MUT agents in accordancewith the invention influence, modulate or control the size of the poolof high-energy electrons, their flux through the ETC, and the generationor dissipation of mitochondrial PMF. Furthermore, formulations inaccordance with the invention influence, modulate, or control secondaryactions involving metabolic intermediates, components of cellularsignaling pathways and subsequent effects upon iron metabolism withinthe cell. These therapeutic interventions include, but are not limitedto: the ability to markedly reduce both de novo as well as secondarygeneration of free radicals; and the ability to modulate intracellularnucleotide levels, ratios, and turnover with subsequent beneficialeffects upon various cell-signaling and other metabolic pathways. Thesecell-signaling and other metabolic pathways include those for proteinkinase C (PKC), diacylglycerol (DAG), the hormone insulin, and thosepathways mediating lipid synthesis. Therapeutic interventions inaccordance with the invention further include the ability to modulatetransitional-metal metabolism, especially copper- and iron-mediatedprocesses related to free-radical biology, and the ability tobeneficially influence transcription factors, including AP-1 and NFKB,which play key roles in inflammation and inflammatory processes.

[0015] The proton-motive force (PMF) is generated by the pumping ofprotons across the mitochondrial membrane out of the mitochondrialmatrix into the inter-membranous space outside the cell. It is coupledwith passage of high-energy electrons down the ETC. The potential energygenerated by this separation of charge drives the production of ATP,which is coupled with proton passage back across the inner mitochondrialmembrane into the matrix. This process collapses the PMF. The generationof reactive oxygen species is strongly dependent upon the magnitude ofthe PMF. Consumption of the PMF diminishes the concentration andhalf-life of semiquinone moieties along the ETC. This reduces the rateof generation of reactive oxygen species, ROS. By collapsing the PMF,MPC serves to uncouple proton pumping from ATP-production. This lowersthe generation of ROS. In the prior art, this insight suggested a keyrole for mitochondrial proton conductance (MPC). The uncoupling ofproton pumping from the metabolism of ATP production formed a basis forregulating ROS in the prior art. In contrast, a primary function of MUTagents and MUT formulations in accordance with the present invention isto limit the accumulation of high-energy electrons potentially availableto the electron transport chain.

[0016] A methodology of metabolic uncoupling therapy in accordance withthe invention comprises: analyzing a specific physiologic process,including delineating the metabolic pathways related to reductivestress; identifying a plurality of MUT agents that modulate themetabolic pathways by influencing electron flux; and formulating acombination of MUT agents that limits the accumulation of high-energyelectrons potentially available to the electron transport chain.

[0017] Further, a method preferably includes selection of MUT agentsbased on their interactions with each other to maximize synergy of theagents. In another aspect, a method includes combining specific amountsand ratios of a plurality of agents in a MUT formulation foradministration in a prescribed manner for a prescribed period of time.Embodiments in accordance with the invention comprise compositions ofchemical compounds, MUT agents, that are useful in metabolic uncouplingtherapy. Selected chemical compounds, chemical species, dietary andpharmaceutical supplements and other nutritional agents (collectively“agents”) in specified amounts, prescribed ratios, and synergisticcombinations are scientifically selected to act at one or multiple focalmetabolic locations to maximize the desired beneficial results, whilesimultaneously minimizing undesired side effects.

[0018] Abnormalities in flux of high-energy electrons, their subsequentmetabolic effects, and induced signaling alterations play pivotal rolesin the delicate balance between health and disease. A method and acomposition in accordance with the invention provide metabolicintervention designed to achieve beneficial modulation of suchprocesses. Embodiments in accordance with the invention treat, improve,and/or normalize various aberrant metabolic pathways central to thedevelopment and progression of numerous diseases including, but notlimited to those named above. Metabolic uncoupling therapy in accordancewith the invention has far reaching beneficial effects on inflammation,glucose and insulin metabolism, mitochondrial function, musclepreservation and hypertrophy, athletic performance, post-exerciseskeletal muscle recovery, hemostasis and thrombosis, development offunctional foods, skin care, vascular disease, neural and cognitivedecline, and bone metabolism, as well as cell, organ, and tissuepreservation.

[0019] MUT in accordance with the invention includes, among othereffects, manipulation of flux of high-energy electrons throughbiochemical pathways; modulation of related cell processes and signalingsystems; modulation of metabolic intermediates involved in theproduction of high-energy electrons (such as semiquinone moieties); andmodulation of nucleotides, nucleotide ratios, and nucleotide cycling.

[0020] MUT agents in accordance with the invention act in variousspecific combinations, compositions, amounts, and ratios to maximizebeneficial effects. Further, MUT in accordance with the inventionminimizes adverse side effects that might otherwise occur throughinappropriate usage of various compounds and compositions not inaccordance with the invention. Because of these beneficial effects, MUTmay be utilized for the prevention of a multitude of conditions, inaddition to its use as a therapeutic modality under conditions ofdisease and aging.

DETAILED DESCRIPTION OF THE INVENTION

[0021] Every animal cell requires regulation of fundamental metabolicprocesses and properties. Cell regulation includes regulating thecontrol, generation, concentration, half-life, energy levels, flux, andrecycling of high-energy electrons, as well as the cellular processesthat high-energy electrons influence, such as nucleotide concentrations,ratios, and redox state. The instantaneous metabolism of high-energyelectrons not only reflects the results of a number of cellularbiochemical reactions, but also directly relates to and regulatescellular phosphorylation and redox status. Abnormalities in thesepathways are typically directly implicated in disease causation.Powerful modulation of these parameters thus is implicitly involved indisease treatment.

[0022] A beneficial intervention of MUT in accordance with the inventiontypically modulates electron flux and related pathways. MUT provides aholistic, multi-modality approach utilizing one or more formulationsdesigned for the treatment of specific and general disease processes. Inanother aspect, MUT provides a method of devising a specificformulation, or combination, of ingredients including MUT agents, and aspecific program of dosage designed for a particular individual at aparticular time in a disease process manifesting in a specific way.Other applications include provision of MUT for various preventativeapplications.

[0023] MUT agents include, but are not limited to, seven groups ofagents described herein. Each group comprises agents sharing a similarfunctional attribute that beneficially modulates one or more biochemicalpathways. This allows the combination of various agents chosen fromdifferent groups that act synergistically in a desired manner. Incontrast, the prior art has not recognized the existence of orformulated distinct groups of agents, each group with differentmechanisms of action, functionality, and synergistic options.

[0024] Each group is defined by a set of functional attributes. Everyagent in each group shares the functionalities of that group. On theother hand, each member of a specific group has a separate, distinctchemical composition. This imbues each agent within a specific groupwith biochemical properties that differentiate it from other agents inthat group. The in-common and the distinct properties of various MUTagents, their association with a specific situation being addressed, thedesired result which is to be achieved, and the metabolic interactionsbetween various agents when used in certain amounts, combinations andratios, and differing clinical considerations dictate the selection ofMUT agents from various groups, and their amounts and relative weightratios. The formulation and dosage of MUT agents depend in part upon theclinical knowledge of one skilled in the art. For example, pharmacologicinteractions between agents under certain biological conditions aresometimes evaluated by one skilled in the art to determine choices ofagents (including amounts, combinations, and ratios) for MUT.

[0025] In contrast, in the prior art, certain compositions of chemicalcompounds were formulated rather simplistically. One, two, or severalspecies were chosen to achieve a desired result. The general thoughtprocess involved the combination of individual chemical compounds, eachof which had been previously shown to have some desired beneficialimpact. Generally, it was believed that if a little was good, more ofeach agent was better. This led to extensive dose-related toxicity,which required backing down the individual doses and was accompanied bya decrement in beneficial action. Since the motivation behind specificagent choices was rarely driven by any basic etio-pathogenic mechanisticunderstanding at the molecular or sub-cellular level, synergies were notapparent, were not recognized, and were not incorporated into the overtdecision-making process for any formulation. This precluded taking fulladvantage of existing, but unrecognized, synergistic interactions.

[0026] One benefit of MUT in accordance with the invention istherapeutic efficacy with minimized dose-related toxicity. Anotherbenefit of enhanced therapeutic efficacy realized in accordance with theinvention involves enhancement of physiologic effect to maximizemetabolic action by customizing the choice of MUT agents to produce acertain specified result in a desired cellular location. This ispossible by selecting agents whose individualized chemical propertiesallow them to localize at a specific location in the cell. For example,certain agents may localize to biological membranes due to theirlipophilic properties, others may be both water and lipid soluble, thusallowing them to cross the cell membrane and build up in the cytosol,while others may specifically localize in the endoplasmic reticulum orthe mitochondrial space. The higher “local” concentration thus producedmay facilitate biological activity without the development of systemictoxicity. Additional possible benefits of this type of “targeted”approach allow more effective utilization of multiple potentialbeneficial attributes of a specific compound. For example, an agent thatlocalizes to the mitochondrial space has therapeutic effects uponelectron flux at this site. If it also has known beneficial effects uponcalcium metabolism, it may have synergistic actions upon mitochondrialcalcium metabolism due to its higher local concentration and multiplebeneficial attributes. The beneficial synergies generated include ahigher “local” concentration at a desired location, more biologicalactivity with less systemic toxicity, and improvement in a relatedphysiologic process (e.g., calcium handling).

[0027] Each group of agents shares a common intra-group functionalitywhich defines the group. The groups as a whole, in addition, sharebeneficial inter-group synergy that contributes to the utility of theinvention. This includes the beneficial regulation and modulation ofhigh-energy electrons. It may be conceptualized as multiple groupsforming an interactive network designed to maximize the metabolic effectby utilizing cross-talk and interaction within as well as betweengroups. The overt benefit of the knowledge of the existence of thesediscrete functional categories is the flexibility in formulatingtherapeutic compositions with better clinical “fit”, enhanced efficacy,improved safety profile and broader applicability. An example involvesthe potentially deleterious effects of excessive reducing power in acell or tissue. Reducing power is ameliorated in accordance with theinvention by decreasing the production of high-energy electrons. It isalso improved by increasing the rate of removal of high-energy electronsas well as by the metabolic “discounting” of the energetic status ofindividual electrons (i.e., the metabolism of NADH to FADH₂). Apreferred embodiment in accordance with the invention may combineseveral or all possible approaches.

[0028] A molecular understanding of the metabolic processes and thepowerful therapeutic synergy of the different functional groups provideadditional insight including, but not limited to, actions affectingmetabolic modulation. The metabolic modulation is achieved by mechanismssuch as diversion to futile cycles, thermogenic electron shuttles,sacrificial consumption, and bio-neutralization. It may also utilizetranscriptional, post-transcriptional, allosteric, substrate-driven,enzymatic, non-enzymatic, cyclic, and linear processes.

[0029] A heightened safety profile associated with embodiments inaccordance with the invention includes preventative formulations. Once adisorder has developed, it already has adverse implications. Thisjustifies the use of potentially toxic therapeutic interventions. On theother hand, in a purely preventative posture, no adverse conditionexists and therefore there is no justification for administration of apotentially toxic regimen. This reasoning forms the basis for expandedapplicability of formulations of MUT agents.

[0030] The prior art failed to evaluate the evolutionary history thatwas responsible for many of today's health woes. With such anevolutionary perspective, it is possible to understand why many of thecurrent health issues arise. Many health problems result from the pooradaptation of our genes (driven by evolutionary forces) to our currentdiet and lifestyle choices. The gene pool that survived the brunt ofevolutionary pressure was forced to make decisions representing acritical compromise. They were forced to balance the generation ofabundant cellular energy with the safe handling of the corrosive oxygenmolecule. The implications of this evolutionary choice plague us today.They also provide prescient insight that facilitates the formation of abeneficial metabolic uncoupling therapy in accordance with theinvention.

[0031] Numerous factors contribute to the selection of MUT agents, aswell as their specific amounts and ratios in a desired formulation.These include, for example, the mechanism driving a specific metabolicpathway, other possible related pathways, and the clinical setting. Forexample, if one pathway is substrate-driven, then a particular amount ofa particular agent is preferred. If an associated pathway isenzymatically regulated and the active agent acts via an allostericmechanism, then a much smaller amount is preferred. If administration ofone agent has an indirect effect of enhancing the bio-availability ofanother agent, this impacts both the absolute levels of each of theagents as well as their respective weight ratio. This knowledge,combined with the need for a specific desired result in a specificclinical setting, is typically utilized by one skilled in the art todirect the construction of a precise formulation designed for a specificclinical condition.

[0032] A central feature of the invention is the use of seven differentfunctional groups of active agents. It is understood that other agentsnot named are also useful in methods and chemical compositions inaccordance with the invention. The seven functional groups areenumerated and defined below.

[0033] Group 1 is characterized by small electrophilic biomolecules.These include TMG (Trimethylglycine), choline, phosphatidyl choline,SAMe (S-adenosyl methionine), carnitine, ALC (acetyl L-carnitine),propionyl carnitine, (myo)inositol, sphingomyelin,glycerylphosphorylcholine, and acetylcholine.

[0034] Each of these molecules differs in its respective chemicalstructure and recognized functions. They do, however, contain a commonchemical moiety. They have a positively charged nitrogen (N) or sulfur(S) atom in their structure, rendering an adjacent methyl group electrondeficient. They react with electron donors in an irreversible reactionby the transfer of a pair of electrons to the electron-deficient methylgroup, thus splitting this group from the positive N or S moiety. Notoxic products are generated by this chemical reaction. This reactiontransforms the electron donor into a more oxidized form (i.e., NADH istransformed into AND+). In this example, the nucleophilic hydride ionfrom NADH is transferred to the electron deficient methyl group of thebiomolecule. This is followed by the splitting off of the methyl groupand the formation of methane associated with the oxidation of NADH toAND+. Since the reaction consumes the biomolecule in the reaction, acontinuous supply is required to maintain the effect.

[0035] The presence of an electrophilic N or S moiety within each agentin this group forms the chemical basis that defines the commonfunctionality of the group. The remaining chemical components of eachagent are otherwise quite variable. This invests them with additional,disparate chemical qualities that may be beneficially utilized in theinvention. For example, choline and phosphatidyl choline (PC) are bothin Group 1, yet PC has a long phosphatidyl group attached to the cholinegroup. This chemical difference defines additional functionaldifferences that influence the relative applicability of each agent toany specific situation. The chemical and functional differences may alsobe important in the determination of specific amounts of an agent usedand its weight ratio with other agents. In this example, PC tends tolocalize to membranes, play key roles in intra-cellular signalingpathways, and impact the function of protein receptors in the membrane.Choline, while possibly affecting membrane metabolism and physiology,plays a more specific role in neurotransmission. Thus, these types ofchemical and functional differences between MUT agents play key roles inthe choices of amounts, types, and ratios of agents.

[0036] Another type of interaction that is important involves the effectof one agent upon the bioavailability of another agent. For example,choline improves the bioavailability of carnitine. If this is the onlyreason for utilizing choline, a specific dose may be chosen in astraightforward manner. If, however, carnitine bioavailability, as wellas neurotransmission concerns, needs to be addressed, this impactsdosing and agent ratio choices. If the specific electron-modulatingaction of choline is also necessary, then greater amounts of choline aretypically chosen, because in these reactions choline is consumed and isnot regenerated.

[0037] Considerations regarding the location of beneficial action (e.g.,which organs are involved—liver or brain; which cells are involved;which intra-cellular location) also affect the intra-group choice ofagents. For example, some agents are not able to cross the blood-brainbarrier very efficiently. This suggests increasing the dosage or usinganother agent to facilitate brain uptake. Thus, embodiments inaccordance with the invention contain selected Group 1 agents, amounts,and ratios to maximize therapeutic benefit.

[0038] Group 2 agents are characterized by anti-consumptive methylagents, including creatine and folic acid. These agents provide acontinuous supply of methyl groups that help replace methyl groups lostby other agents while performing their prescribed role. For example,Group 1 agents are typically consumed, and not regenerated, as they areutilized in the invention. A Group 2 agent provides replacement for theongoing loss of methyl groups from, for example, the Group 1 reactions.

[0039] Group 3 agents are characterized by biological macromolecules,including DHA (docosahexanoic acid), EPA (eicosapentanoic acid), andalbumin. These are molecules that by their size, configuration, numbersof disulfide bonds, or a combination of these features undergo chemicalreduction. That is, they are electron acceptors, sometimes at onemolecular location, but typically at multiple separate locations in eachof the molecules. These reactions are either reversible or irreversible.When irreversible, then once all the sites available for acceptance ofelectrons are consumed, they are removed and biologically recycled. Inthis sense, they are large, sacrificial, anti-reductive biologicalcompounds. DHA and EPA are both long-chain fatty acids. Albumin is aprotein. These structural differences make them useful in differentlocations. Albumin is primarily a plasma protein, and the fatty acidsare usually found in cellular biomembranes. DHA has more pronouncedstructural utility, and EPA is involved in cellular signal-transductionpathways. The fatty acids have different numbers of double bonds, whichalso affect their chemical reactivity. EPA modulates membranephospholipase activity and membrane turnover. Agent composition, amountsand ratios also depend upon such factors as the clinical condition beingtreated, the degree of inflammation present, and the omega-6/omega-3ratio, as well as absolute levels of omega-6 and omega-3.

[0040] Group 4 agents are characterized as oxaloacetate (OAA)precursors, including PYR (Pyruvate), ASP (Aspartate), GLY (Glycine),and SER(Serine). These are all small amino or alpha-keto acids, whichare biochemical precursors of oxaloacetate via differing pathways andunder different metabolic conditions. This is significant because of theability of OAA to function as an electron-acceptor in association withthe oxidation of NADH to AND+. Depending upon the prevailing chemicalenvironment in the cell, one agent may be selected over others due toits preferred metabolism to OAA. Other factors useful in thedetermination of one of these agents over another also involve othermetabolic pathways they modulate or in which they react. These aredifferent from agent to agent and involve considerations involvingenergy generation, protein synthesis, neurotransmission, andphospholipid synthesis, and may also include electron-shuttle function.Some of the functions of Group 4 agents involve allosteric modulation ofenzymes, substrate-driven reactions, cyclic pathways orpost-transcriptional modification. The selected function of a Group 4agent in any specific circumstance is influenced by the clinicalsituation and the desired result. Together these considerations guidethe specific choices regarding combinations of agents, amounts andratios.

[0041] Group 5 agents are characterized by B vitamins and structurallyrelated entities, including folate, riboflavin, B1, B3, niacinamide,nicotinamide, polynicotinate, B6, B12, biotin, pantothenic acid, andother related chemical species.

[0042] These compounds comprise the B-vitamin group and includepyrimidine, pyrazine, and other aromatic rings. They are able to undergoreductive addition reactions. Selection of one entity over another isdetermined in part by other B vitamin properties, (e.g., the enzyme forwhich it acts as a co-factor, location of the enzyme, effects uponcyclic GMP and other separate biochemical profiles). Selection of Group5 agents is also influenced by the close functional association among Bvitamins and their own internal synergy.

[0043] Group 6 agents are characterized by electron cycling agents,including coenzyme Q10, lipoic acid, and acetoacetate.

[0044] These compounds are easily cycled by accepting and then releasingelectrons. This process modulates the NADH redox state, alters otherbiochemical characteristics of each agent, and forms a cyclic ratherthan linear biochemical pathway. In addition to their sharedelectron-cycling properties, they each have different chemical traitsmanifested under differing conditions. These factors help direct agentchoices from this group. Coenzyme Q10 is found primarily withinmembranes, and is frequently associated with the electron transportchain along the inner portion of the inner mitochondrial membrane. Italso has anti-oxidant functionality. Lipoic acid is both water and lipidsoluble and has access to most biological compartments. Also, by being acofactor for enzymes, it plays a central role in energy generation andmechanisms of glucose and insulin metabolism. Lipoic acid is able tobind transition metals, thereby modulating their role in numerousimportant physiological reactions. Acetoacetate is a ketone body used asa fuel source and a precursor of neurotransmitters, and it has access tothe brain compartment.

[0045] Group 7 agents are characterized by iron-binding agents, such aspolyphenolic agents and desferoximine.

[0046] The reduction of ferric to ferrous ion facilitates the release ofan iron atom from protein-binding agents (e.g., ferritin). This causesthe iron transition metal to act catalytically by facilitating thegeneration of electrons, which contribute to the production of ROS andsubsequent tissue damage. This damage involves disruption of DNA, lipidstructures, and proteins. Group 7 agents have the ability to bind andinactivate free iron. This forms the basis for their beneficial actions.Polyphenolic compounds also are powerful anti-oxidants, modulate manyintra-cellular signaling pathways, and protect lipoproteins fromoxidative stress. Preferably, these additional properties are consideredin the selection of Group 7 agents.

[0047] Therapeutic combinations of MUT agents are formulated inaccordance with the invention by selection of:

[0048] two or more agents from Group 1;

[0049] one or more agents from Group 4;

[0050] two or more agents from Group 5; and

[0051] one or more agents from Group 6.

[0052] Certain embodiments in accordance with the invention also includeone or more MUT agents from Groups 2, 3, and 7.

[0053] Listed below are exemplary MUT agents and dosage ranges used inmolecular uncoupling therapy in accordance with the invention. Inpreferred embodiments, a plurality of MUT agents are used incombination. MUT Agent Daily Dose Range Daily Dose Preferred Greatine 10 mg to 30 g  1 g to 10 g Acetylcholine  1 mg to 1 g  10 mg to 500 mgPropionyl L-carnitine  1 mg to 10 g  20 mg to 2 g Myo-inositol  10 mg to10 g 100 mg to 2 g Pyruvate (Pyruvic acid)  50 mg to 30 g 500 mg to 20 gAspartate (Aspartic acid)  50 mg to 30 g 500 mg to 20 g Serine  50 mg to30 g 500 mg to 20 g Glycine  50 mg to 30 g 500 mg to 20 g Coenzyme Q10 1 mg to 2,000 mg  10 mg to 800 mg Alpha Lipoic Acid (Lipo-  1 mg to4,000 mg  10 mg to 1,400 mg ic acid, r lipoic acid, r alpha lipoic acid,rademic mixture) Eicosapentanoic Acid  10 mg to 4,000 mg  50 mg to 2,000mg (EPA) Docosahexanoic Acid  10 mg to 4,000 mg  50 mg to 2,000 mg (DHA)Trimethylglycine (TMG) 100 mg to 5,000 mg 500 mg to 3,000 mgDimethylglycine (DMG) 100 mg to 5,000 mg 500 mg to 3,000 mg Choline  25mg to 6,000 mg 100 mg to 2,000 mg Phosphatidy Choline I  25 mg to 20 g500 mg to 5 g SAMe  10 mg to 3,000 mg 100 mg to 1,600 mg Folic Acid(folate) 100 mcg to 20 mg 400 mcg to 10 mg Riboflavin  1 mg to 100 mg  5mg to 30 mg B1  1 mg to 400 mg  10 mg to 100 mg B3  1 mg to 4,000 mg  10mg to 2,000 mg B6 or pyridoxine  1 mg to 400 mg  10 mg to 200 mg(pyridoxyl phosphate) B12  10 mcg to 1,000 mcg  20 mcg to 500 mcg Biotin 10 mcg to 20 mg 300 mcg to 12 mg Pantothenic Acid  1 mg to 1,000 mg  10mg to 250 mg (pantothenate) Carnitine  5 mg to 20 g  20 mg to 10 g 5Acetyl L-carnitine  1 mg to 10 g  20 mg to 10 g Polyphenolic anti-  1 mgto 2 g  20 mg to 1 g oxidants Sphingomyelin  5 mg to 5 g  20 mg to 2 gGlyceryl phosphoryl  5 mg to 6 g  20 mg to 4 g cholineMagnesium-creatine  10 mg to 50 g  50 mg to 20 g 10 Albumin  10 mg to100 g  20 mg to 50 g Acetoacetate  10 mg to 300 g  50 mg to 100 g 10

[0054] Listed below are exemplary MUT agents and corresponding agentratios in accordance with the invention. Agent Ratios Range Creatine/TMG1/20 to 30/1 Creatine/Carnitine 1/10 to 250/1 Creatine/Pyruvate 1/20 to25/1 Creatine/Aspartate 1/10 to 25/1

[0055] Many of the agents listed may occur in long polyene chain form.These are also to be included in the invention. Such formulations mayinclude, for example, poly(ene) phosphatidyl choline.

[0056] In general, referral to a specific agent is to be understood asreferring to all forms of that agent. For example, the terms niacin,niacinamide, nicotinamide, and polynicotinate are essentiallysynonymous. Similarly, the term “alpha lipoic acid” (ALA) refers tolipoic acid, thiotic acid, R alpha lipoic acid, and racemic mixturesthereof.

[0057] An imbalance in the pool of high-energy electrons inducesabnormalities in numerous pathways of cellular metabolism and plays akey role in the development of pathologic states. One common abnormalityof cellular metabolism involves development of reductive stress, thatis, increased electron pressure from too many high-energy electrons.Reductive stress impacts intracellular signaling systems that arecausally related to metabolic health problems.

[0058] Intracellular accumulation of triglyceride (TG) occurs early innumerous diseases. Accumulation of TG is clearly a risk factor for thesubsequent development of obesity and the associated abnormalities ofglucose and insulin metabolism. TG content has been correlated withintracellular long chain fatty acyl CoA (LCAcCoA) content. Accumulationof LCAcCoA is suspected to increase production of diacylglycerol (DAG),a potent stimulator of Protein Kinase C (PKC) isoenzymes. Certain PKCactivity inhibits the intracellular insulin-signaling pathway andimpairs insulin-stimulated glucose transport; that is, it causes thedevelopment of insulin resistance, the cornerstone involved in theetiology of a host of metabolic diseases present today in epidemicproportions. Intracellular TG buildup is treatable by MUT in accordancewith the invention.

[0059] Alterations in cellular redox status modulate a number ofimportant intracellular metabolic processes. At any point in time, eachcell resides in a particular redox state. Redox states fall along acontinuum of values. Intracellular nucleotide ratios determine wherealong this continuum each cell resides at any particular instant. Mostcells generally tend to function in a relatively reduced biochemicalstate. When the cell becomes even more biochemically reduced, it movesin the direction of reductive stress. Reductive stress may be defined asan abnormally increased electron pressure or “reducing power”. Ittypically occurs either as a result of pathological processes leading toan excess of high-energy electrons, or a failure of mechanisms availablefor dealing with this rise in electron pressure, or both. It wasrecognized by the inventor that reductive stress is not only more commonthan oxidative stress, but it is also the main source of production ofreactive oxygen species (“ROS”) and reactive nitrogen species (“RNS”) inthe body.

[0060] A beneficial effect of substances containing reducible groups,which relieve this electron pressure, defines a category ofanti-reductants. The in vivo action of compounds capable of oxidizingNADH to AND+ is analogous to the in vitro action of electron acceptorssuch as methylene blue.

[0061] Abnormalities in the functioning of the Krebs cycle and theelectron transport chain are attributable to reductive stress. In thiscontext, it is important to realize that stress induced by reductiveconditions or a diet deficient in anti-reductive components causesidentical pathological states. For example, ethanol-induced reductivestress in liver, or a diet deficient in electrophilic groups, producesthe same disorders. Regardless of its cause, reductive stress leads toundesirable accumulation or generation of reactive oxygen species (ROS),to hypomethylation of DNA, and to impaired oxidation of triglyceride(TG).

[0062] Vasodilation and increased blood flow are the earliest vascularchanges associated with diabetes and also with acute hyperglycemia innon-diabetic humans. These changes are associated with an increase inthe NADH/AND+ ratio. Increased glycolysis is associated with anincreased cytosolic NADH/AND+ ratio. The mechanism behind theassociation of augmented glycolysis and elevation of the NADH/AND+ ratioappears to result from a dys-equilibrium between the rate of oxidationof glyceraldehyde 3-phosphate (“GAP”) to 1,3 diphosphoglycerate (“1,3DPG”), which is associated with the reduction of AND+ to NADH, and therate of reduction of pyruvate to lactate (coupled with the oxidation ofNADH to AND+).

[0063] Metabolic consequences of an increase in the cytosolic ratioNADH/AND+ impact the activity of numerous cytoplasmic and mitochondrialenzymes that utilize NADH and AND+ as cofactors and/or are regulated bythem. This is associated with several disorders of lipid metabolism.These include increased de novo synthesis of DAG and subsequentactivation of PKC. These alterations have been linked to many metabolicand functional vascular and neural changes. Inhibition of fatty-acidoxidation and increased lipogenesis are associated with an increase inmitochondrial NADH/AND+ ratio.

[0064] Elevation of the cytosolic NADH/AND+ ratio is associated withintracellular increases in glycolytic triose phosphate compounds, whichcause increases in DAG with subsequent activation of PKC isoforms. ThesePKC isoforms lead to the development of insulin resistance and producedetrimental effects upon the insulin-signaling pathway.

[0065] In accordance with the invention, alteration of NADH levels ormodulation of the NADH/AND+ ratio occurs by supplementation with variousanti-reductive compounds in Groups 1 through 6. This tends to oxidizeNADH to AND+, thus lowering the NADH/AND+ ratio, which produces a fallin lipogenesis and has a deactivating effect upon PKC.

[0066] A more oxidized NADH/AND+ ratio also tends to down-regulate theNADH oxidase system and tends to keep coenzyme Q10, an electronacceptor, in a relatively more oxidized state. Both of these mechanismspotently down-regulate production of harmful ROS and RNS.

EXAMPLE 1

[0067] An exemplary embodiment in accordance with the invention suitablefor metabolic uncoupling therapy of hepatic steatosis/steatohepatitiswas formulated. Daily administration of a composition containing thefollowing ingredients is recommended for a period of time necessary toachieve a desired result, typically for a time period in a range of fromtwo months to twelve months, or until resolution of the hepatic fataccumulation and/or inflammation. Two doses to three doses per day areused. One composite daily dose contains: Coenzyme Q10 100 mg R alphalipoic acid 300 mg Eicosapentanoic acid (EPA) 1 g Trimethylglycine 500mg Phosphatidyl choline 3 g S-adenosyl methionine (SAMe) 200 mgCarnitine 500 mg Aspartic acid 2 g Vitamin B1 25 mg Vitamin B2 25 mgVitamin B3 25 mg Vitamin B5 25 mg Vitamin B6 25 mg Folic acid 800 mcg

[0068] A dose may also include: Biotin 1 mg Hydroxycitric acid 500 mgVitamin B12 1 mg

[0069] The clinical condition hepatic steatosis/steatohepatitis, as wellas the primary and secondary chemical actions and physiologicfunctionalities of each of the available agents, were considered inselecting agent composition, amounts and ratios. EPA is a beneficial MUTagent for therapy of hepatic steatosis/steatohepatitis, but alsofacilitates fat burning by other actions that include the inhibition ofacetyl CoA carboxylase (ACC) and the activation of carnitine palmitoyltransferase (CPT). Increased fat burning, especially in the liver,lowers the intracellular hepatocyte fat content and ameliorates thecondition. Coenzyme Q10, in addition to modulating electron flux, actsas a potent anti-oxidant with anti- inflammatory actions. It alsoimproves activity of the electron transport chain, thus up-regulatingreverse electron transport. This discounts the energy status ofelectrons, further speeding up fat burning as well as oxidizing theQ-couple. This decreases the generation of oxidative stress, therebyindirectly down-regulating the hepatic inflammatory process. Aspartate,another MUT redox-active agent, additionally increases hepatic fatburning by up-regulating futile, thermogenic carbohydrate cycles, whichdecreases the intra-cellular fat burden. This further down-regulates theinflammation typically present under these conditions. Carnitine, aGroup 1 agent, also is used as a cofactor for the transport of activatedlong-chain fatty acids into the mitochondria where they undergo completeoxidation. B vitamins, Group 5 agents, in addition to their primaryactions as described above, are useful cofactors for many of theenzymatic pathways involved in the overall therapeutic process. Thesenumerous individual modulations act synergistically to maximize hepaticfat burning, further down-regulating hepatic fat stores and associatedinflammation.

[0070] The selection of the MUT agents of Example 1 exemplifies howmethodical selection of agents facilitates the synergy deriving from thecombined activity of the primary (related to handling of high-energyelectrons) and secondary (synergistic actions unrelated to the primaryeffects) actions of the MUT agents. By combining the metabolicuncoupling therapy agents into a formulation that merges the effectswith the other additional, implicit, synergistic, beneficial functionsof the specifically chosen agents, the functionality of the formulationis maximized.

[0071] Prior art formulas sometimes included individual isolated agentssimilar to a MUT agent, or combinations of agents, known in the priorart to improve specific global clinical endpoints, such as hepatic fatcontent. Nevertheless, because the prior art failed to consider thedetailed molecular mechanisms involved, including the primary andsecondary interactions at the cellular level, the prior art did notanticipate the additional beneficial secondary actions of MUT inaccordance with the invention. Such benefits of MUT result from novelconsiderations of metabolic molecular actions which are not otherwiseapparent. The prior art did not recognize or teach the molecularsynergies described in this specification. These include, but are notlimited to, numerous influences of the redox state on metabolicpathways, and the detailed mechanisms available for the therapeuticmodulation of the redox state at many levels and many sites. Themolecular synergies provided by embodiments in accordance with theinvention include the beneficial, functional, molecular interactionscharacterizing each of the defined Groups 1 through 7, the secondaryactions of each agent, including their metabolic interactions with theprimary molecular effects of each of the MUT active agents, and thesynergy accruing from the inter-group interactions. The selection andapplication of the interactions, along with the ability to intercede inmetabolic pathways and mechanisms in controlled and precise ways, is abenefit of embodiments in accordance with the invention.

EXAMPLE 2

[0072] Another exemplary embodiment in accordance with the inventionsuitable for metabolic uncoupling therapy of hepaticsteatosis/steatohepatitis was formulated. Daily administration of acomposition containing the following ingredients is recommended for aperiod of time necessary to achieve a desired result, typically for twomonths to twelve months, or until resolution of hepatic fat accumulationand/or inflammation. Two doses to three doses per day are used. Asdiscussed above, certain MUT agents provide synergistic secondarybenefits when chosen and combined in specific amounts and ratiosdesigned for indicated uses. Pyruvate and EPA have secondary actions asoutlined above. Green tea leaf extract lowers the respiratory quotient(RQ) by beneficially modulating the amount of fat the body burns. Itincreases fat burning and decreases the content of intracellular fat. Italso has anti-inflammatory activity. Pyruvate, in addition to oxidizingNADH to decrease the NADH/AND+ ratio, also augments fat oxidation andinhibits fat storage. Creatine, in addition to facilitating methyl groupavailability, also indirectly turns on the enzyme AMP kinase (AMPK),which further augments fat burning (aside from its MUT effects). Thechoice of multiple B vitamins beneficially modulates MUT activity. Theyalso have beneficial secondary actions mediated via their roles asenzyme cofactors, stress reducers, and anti-inflammatories. One dosecontains: Creatine 2 g R alpha lipoic acid 200 mg SAMe 400 mg EPA 500 mgTMG 500 mg Green tea leaf extract 20 mg Pyruvate 3 g Phosphatidylcholine 2 g ALC 500 mg Vitamin B1 25 mg Vitamin B2 25 mg Vitamin B3 25mg Vitamin B5 25 mg Vitamin B6 25 mg Folic acid 800 mcg

[0073] A dose may also include:

[0074] Conjugated linoleic acid (CLA) 2 g

EXAMPLE 3

[0075] An exemplary embodiment in accordance with the invention wasformulated for achieving weight loss using metabolic uncoupling therapy(MUT). Two doses to three doses per day are recommended. Additionalbeneficial attributes are included in this formulation. Fat burning isaugmented by utilizing properties in addition to the MUT properties ofthe agents chosen for this formulation. These include the fact thataspartate increases hepatic fat oxidation utilizing mechanisms describedabove. Carnitine increases carnitine palmitoyl transferase (CPT)activity. Choline acts to increase carnitine levels. This actssynergistically to increase fat burning. Each dose contains: Asparticacid 2 g Biotin 600 mg HCA 500 mg Chromium 400 mcg Carnitine 25 mgCholine 500 mg TMG 200 mg SAMe 200 mg ALA 200 mg B1 25 mg B2 25 mgFolate 1 mg Niacinamide 275 mg Creatine 1 g

[0076] Each dose may include medium chain triglycerides (MCT). MCT 10 g

[0077] These augment the activation of futile, thermogenic carbohydratecycles, further adding to the weight loss activity.

EXAMPLE 4

[0078] An exemplary embodiment in accordance with the invention wasformulated for treating hyperlipidemia using metabolic uncouplingtherapy (MUT). Two doses per day are recommended. Each dose contains:Pyruvate 2 g Aspartic acid 1 g HCA 250 mg ALC 1 g ALA 150 mg TMG 750 mgCholine 250 mg Inositol 600 mg Coenzyme Q10 100 mg Guggulipid 750 mgTocotrienols 50 mg Biotin 1 mg Folate 1 mg Pantothenic acid 50 mgPyridoxine 50 mg

[0079] A dose may also include conjugated linoleic acid (CLA): CLA 1 g

[0080] By its activation of peroxisome proliferator associated receptors(PPAR), CLA further enhances beneficial effects upon hepatic fatoxidation and VLDL secretion.

[0081] Agents chosen for this formulation were selected for theirability to effect a reduction in high-energy electron flux, as well asfor concomitant secondary actions, which act to prevent the developmentof hyperlipidemia. Pyruvate and aspartic acid were both chosen toactivate the generation of OAA, thereby facilitating the flux herhigh-energy electrons through thermogenic pathways. The resultingincreased flux of high-energy electrons into thermogenic pathwaysenhances hepatic fat oxidation and is associated with diminished hepaticsynthesis and secretion of very low-density lipoproteins (VLDL).Pyruvate further increases hepatic fat burning by independent activationof the dihydroxyacetonephosphate-alpha glycerolphosphate shuttle. Thishas synergistic beneficial actions upon hepatic VLDL secretion. Pyruvateand aspartic acid also contribute to weight loss. This weight loss actsindependently to prevent hyperlipidemia, and also down-regulates hepaticlipoprotein synthesis and secretion. Choline increases endogenouscarnitine levels and bioavailability, which further augments hepatic fatoxidation. This also improves the hyperlipidemic state. This activity isindirectly synergistic with the pyruvate action upon lipoproteinsynthesis and secretion.

EXAMPLE 5

[0082] An exemplary embodiment in accordance with the invention wasformulated to inhibit the development of Type II diabetes usingmetabolic uncoupling therapy (MUT). Type II diabetes is a prototypicaldisorder manifesting increased electron pressure. MUT is, therefore,especially well-suited for its therapy. Two doses per day arerecommended. Each dose includes: Coenzyme Q10 30 mg R alpha lipoic acid300 mg EPA 200 mg Chromium 100 mcg Selenium 100 mcg Aspartate 2 g Biotin1 mg Creatine 500 mg L-Arginine 1.5 g Pyridoxine 50 mg Folic acid 1 mgThiamine 100 mg Carnitine 500 mg TMG 500 mg Glycerylphosphorylcholine500 mg Phosphatidyl Choline 500 mg

[0083] Several of the chosen agents have known properties that act toprevent the development of Type II diabetes by means unrelated to theirmetabolic uncoupling actions. Coenzyme Q10 is a mitochondrialanti-oxidant and membrane stabilizer. It also facilitates pancreaticinsulin release. EPA and aspartate have potent weight loss effects.Obesity plays a key role in the development and progression of Type IIdiabetes and weight loss is a cornerstone of anti-diabetic therapy.Creatine lowers homocysteine levels. This reduces the inflammatory statethat is a recognized risk factor for the development and progression ofType II diabetes. R-alpha lipoic acid improves insulin sensitivity andmarkedly diminishes the probability of developing Type II diabetes.Selenium is also a potent insulin sensitizing agent and actssynergistically with ALA. ALA also is therapeutic for diabeticneuropathy. Since redox stress is one of the early markers of thediabetic state, the utility of a program designed to modulatespecifically and beneficially this pathophysiologic condition innumerous, complementary ways offers benefits not otherwise disclosed inthe prior art.

EXAMPLE 6

[0084] An exemplary embodiment in accordance with the invention wasformulated for treating inflammatory gastrointestinal disease usingmetabolic uncoupling therapy (MUT). Two doses per day are recommended.In addition to facilitating MUT, several agents from specific groupscentral to the invention were chosen because they possessed additionalhelpful, secondary properties of benefit in the therapy of inflammatorygastrointestinal disease. These include EPA, which reduces the incidenceof mucosal polyp formation. Phosphatidyl choline, in addition to itsprimary actions, reduces inflammation due to aspirin and NSAIDs(non-steroidal anti-inflammatory drugs). Stress frequently accompaniesinflammatory intestinal disease. Pyridoxyl phosphate down-regulatesstress-mediated pathways. Higher doses of choline and PC were utilizedbecause of the large size of the lesions. Each dose includes:Phosphatidyl choline 4 g Choline 2 g Glycine 500 mg Glutamine 2 g Ralpha lipoic acid 100 mg Niacin 200 mg Folate 1 mg Pyridoxal phosphate50 mg SAMe 100 mg ALC 150 mg CLA 2 g EPA 2 g Green tea leaf extract 50mg Vitamin B12 100 mcg Vitamin A 2500 IU Vitamin D 400 IU Vitamin E 200IU

[0085] The development of cognitive dysfunction is often associated witha fall in intra-neuronal AND+ concentration. Oral provision ofniacinamide as a single agent tends to improve AND+ levels. There are,however, more effective mechanisms for maintenance of AND+ levels inneurons than just isolated administration of niacinamide. The mechanismsare also associated with less toxicity. The related molecular mechanismsinfluence AND+ levels as well as mechanistically related pathways. Asynergistic combination of MUT agents maximizes therapeutic efficacy andminimizes toxicity. MUT compositions are based upon a detailedunderstanding of metabolic pathways involving the flux of high-energyelectrons and their relationship with AND+ metabolism. The choice ofniacinamide as an AND+ precursor is appropriate because of its enhanceduptake by the brain. However, the sole administration of niacinamide isinappropriate because even very high dosing lacks the therapeutic actionof a directed multi-modal approach. Single drug therapy is alsoaccompanied by toxicity in a large percentage of potential candidatesfor such treatment.

EXAMPLE 7

[0086] An exemplary embodiment was formulated in accordance with theinvention to enhance cognitive function. Four tablets per day arerecommended. These may be administered in a divided fashion as twotablets twice per day. The inclusion in the formulation of relativelysmall doses of multiple, active agents, each of which beneficiallymodulates the involved pathways, obviates the usage of high doses of asingle (potentially toxic) agent. A fall in AND+ concentration resultsfrom a lack of adequate amounts of precursor, from deficient activationand transformation of the substrate into AND+, from excessivedestruction or consumption of any AND+ present, and from impropermetabolism in the involved pathways. Thus, there are a number of sitesavailable for safe intervention to augment AND+ levels. In addition tothe multiple sites available for therapeutic intervention, there existmultiple ways to beneficially enhance AND+ levels at each localeutilizing principles inherent in MUT. Four tablets include:Glycerylphosphorylcholine 1,000 mg Creatine 1,000 mg ALC 500 mg ALA 100mg Folic acid 800 mcg B2 30 mg Niacinamide 200 mg B6 100 mg B12 5 mgThiamine 25 mg Coenzyme Q10 50 mg Phosphatidyl choline 50 mg Choline 500mg TMG 100 mg Pyruvate 150 mg

[0087] Group 1 agents oxidize the NADH/AND+ couple, thus augmenting AND+levels. The specific agents chosen have a predilection for localizationin the brain. This increases the local brain concentration at the activesite. They also play additional key roles in brain metabolism in statescharacterized by falling AND+ levels. These include metabolism ofmembranes, neurotransmitter production, and energy generation.

[0088] Additional beneficial, synergistic actions of the agentsspecifically chosen for this formulation are discussed below. Lipoicacid (ALA) and coenzyme Q10 were both included for their effects uponAND+. Lipoic acid facilitates cerebral energy generation as a cofactorin enzymes involving these processes. It also acts as a detoxifyingagent and facilitates the metabolism of glucose, the predominant fuelsource in the brain. Creatine improves cerebral energy generation. ALCimproves brain energy production and acts as a source of acetyl groups.It up-regulates CoA levels and activates the pyruvate dehydrogenasecomplex (PDH). This is the primary regulatory enzyme in the pathway ofoxidative glucose metabolism. Coenzyme Q10 increases the number ofmitochondria in neurons, is a mitochondrial electron chain constituent,and a mitochondrial anti-oxidant. Niacinamide is a direct precursor ofAND+, but was able to be used in smaller, safer amounts than typicallyused in the prior art. Other B vitamins, key players in cerebral energygeneration as well as active MUT agents, were also included. Vitamin B6helps protect the brain against the stress of falling AND+concentrations. The benefits of a MUT formulation over prior art includeexpanded safety profile, enhanced efficacy, utility of synergisticprimary and secondary actions, and enhancements based upon specifictissue compartmentalization and augmented concentrations at the activesites.

EXAMPLE 8

[0089] An exemplary embodiment in accordance with the invention wasformulated as a brain performance-enhancing drink mix. This ispreferably used during athletic competitions, such as golf matches,under stressful work conditions, around school exam times, or in othersimilar circumstances. One or two doses per day are recommended. Anindividual dose includes: NaCl 225 mg NaHCO₃ 175 mg K₂HPO₄ 75 mg KHCO₃175 mg MgSO₄ 150 mg Mg citrate-monohydrate 100 mg Glucose 10 g LipoicAcid 25 mg Phosphatidyl choline 100 mg ALC 40 mg Mg-creatine chelate 2 gTMG 100 mg Choline 100 mg Glycine 50 mg Huperzine A 50 mcg Chromium 50mcg Selenium 50 mcg Thiamin 50 mg Niacinamide 150 mg Pantothenic acid 30mg Riboflavin 20 mg Pyridoxal phosphate 20 mg Vitamin B12 5 mg Folicacid 1 mg Natural cherry flavor

[0090] As stated above, this product is primarily, although notexclusively, designed for use to enhance brain function during stressfulperiods. At these times, cortisol levels are frequently elevated. Underthese conditions, the ability of the brain to use glucose, its main fuelsource, is impaired. This exacerbates situations of inadequate fuelsupply, deficiencies in energy production, neurotransmission, excessivefree radical production and membrane repair. In a comprehensive approachin accordance with the invention, each of these abnormalities isaddressed. This leads to stacking the formulation with MUT agents thataddress the primary problem. Since there are simultaneously quite broadrequirements in many other areas of brain metabolism, the agents chosenhave multiple beneficial functions that address these needs cogently. Inaddition, the selected agents preferably cross the blood-brain barriereasily.

[0091] Because glucose availability and metabolism are important in thissituation, glucose was included as an ingredient in the formulation.Pyridoxal phosphate was included for its beneficial modulation of thestress state and elevated cortisol concentrations. Since energygeneration was impaired, all the B vitamins were included for theirsecondary roles in energy generation, as well as for their primary rolesin modulation of high-energy electron flux. Chelated magnesium creatinewas included not only for its ability to augment methyl groupavailability, but also to improve cerebral energy generation directly.Magnesium is important for many steps in energy production. ALA ismultifunctional in these circumstances. It helps with energy generation,redox status, inflammation, transition metal handling, and in a role asan anti-oxidant that easily crosses into the brain and has activity inthe cytosol as well as in lipid domains. Huperzine A crosses easily intothe brain and improves cholinergic neurotransmission. ALC providesacetyl groups, up-regulates CoA levels, and improves cerebral energygeneration. Choline acts as a precursor for the neurotransmitteracetylcholine and membrane phospholipids. Lipoic acid increasesintracellular glutathione levels. This facilitates cellular anti-oxidantfunction. As may be seen in this example, the complexity of the problemwas evaluated and the composition of the formulation was developed inaccordance with the invention to address the complex problem.

[0092] Various neurodegenerative disorders are amenable to combinationsof MUT agents. Such disorders include multiple sclerosis and Alzheimer'sdisease, but MUT formulations are applicable generally to a broad rangeof similar disorders. Many neurodegenerative disorders are characterizedby the accumulation of non-digestible cellular remnants. These may formas the result of non-enzymatic oxidative cross-linking reactions thatmetabolically transform proteinaceous or other compounds into wasteproducts that build up over time. These disorders are calledproteopathies.

[0093] Multiple sclerosis is generally believed to be an inflammatorydisorder of unknown etiology affecting the myelin sheath of nerves.Sphingomyelin is one of the major lipids in the myelin sheath. It isalso an endogenous electron-accepting compound (analogous to the Group 1MUT compounds described in the specification) and acts as a sink forhigh-energy electrons. Sphingomyelin's principal biological function isto enable nerve cell transmission by its action in the myelin sheath. Ifit is consumed while acting as a protective high-energyelectron-accepting compound, it is no longer available to perform itsmain function, and nerve damage occurs.

[0094] Hydroxyl ions have significant reducing potential, as shown bytheir detoxification via reaction with the oxidized disulfide groups inalbumin. Hydroxyl ions are present in the inflammatory reaction seen inmultiple sclerosis. They play a key role in myelin breakdown. Whenpresent in sufficient quantity, sphingomyelin binds the high-energyelectrons supplied by the hydroxyl ions in a sacrificial act thatneutralizes the hydroxyl radical. The sphingomyelin is consumed in theprocess, thereby degrading the structure and function of the myelinsheath.

[0095] Selected MUT agents also quench hydroxyl ions (e.g., through thetendency of hydroxyl ions to react with the positive nitrogen atom inthe trimethylnitrogen moieties in the structures of the Group 1 agents).As this happens, methane is released. The anti-reductant agents therebyserve as sacrificial neutralizers of the hydroxyl ions (or other ROS).This inhibits or prevents the loss of sphingomyelin and preserves theintegrity of the myelin sheath.

[0096] In Alzheimer's disease, decreases in the acetylcholine content ofthe brain are an early, and consistent, finding associated withdisastrous functional consequences. Oxidative stress has been implicatedearly in the course of Alzheimer's disease, and hydroxyl ion activityhas also been documented. Acetylcholine, like sphingomyelin, has apositively charged trimethylnitrogen group and in all likelihoodsacrifices itself as a partial defense against deleterious compoundspossessing unpaired electrons. This adversely affects the function ofcholinergic (acetylcholine mediated) neurotransmission. Thisneurological system helps mediate memory function and cognitiveprocessing. Therapy for Alzheimer's disease, in accordance with theinvention, utilizes combinations of electron-accepting compounds. Theyfunction as substitute electron acceptors for the acetylcholinemolecules. In so doing, the acetylcholine molecules are preserved fortheir primary functions in the brain.

[0097] Apoptosis is another common feature of neurodegenerativeprocesses. It is a delayed form of cell death brought about byactivation of an energy-requiring suicide program inherent inmulticellular organisms. Various mechanistic explanations for thisexist, but the exact pathways involved are not fully understood.Elevated AND+ levels are involved in DNA repair. DNA damage (as seen instates of oxidative stress) is known to activate poly (ADP-ribose)polymerase (PARP), which utilizes AND+ as a substrate. This results inAND+ depletion, and subsequently ATP depletion, due to futile activationof energy-consuming AND+ re-synthetic pathways. ATP depletion is knownto be one of the central factors leading to the induction of apoptosis.Reductive stress, in the presence of oxygen, typically generates ROS,including hydroxyl radicals. This may activate apoptotic pathways.

[0098] Nerve growth factor (NGF) is one of the only known agents thatprevents apoptosis of cells in culture. Currently, NGF must beadministered by intracranial injection. This provides a significantimpediment for broad clinical utility. In contrast, MUT agents whichincrease AND+ (and thus decrease the NADH/AND+ ratio), may be takenorally and have easy access to the central nervous system. Augmentationof AND+ levels prevents DNA damage. In addition, AND+ has been reportedto inhibit calcium-magnesium endonuclease, which fragments DNA when itis activated during the apoptotic process. High AND+ levels alsofacilitate DNA repair. The anti-reductant activity of individual agentsin Groups 1 to 6 increases AND+ levels.

EXAMPLE 9

[0099] A multifunctional combination for augmenting AND+ levels wasformulated. Typically it is administered two to three times per day foran effective period of time. One dose includes: Niacinamide 500 mg ALC500 mg Inositol 250 mg Choline 250 mg Phosphatidyl choline 500 mgGlycine 50 mg Lipoic acid 100 mg Coenzyme Q10 30 mg Vitamin B1 10 mgPyridoxine 10 mg Pantothenic acid 10 mg Glycerylphosphorylcholine 150 mgEPA may also be included 100 mg

[0100] This formulation is heavily stacked with sacrificialelectron-accepting agents, each of which are able to recycle NADH toAND+. Their similar biochemical functions act synergistically in thisregard. This fact, coupled with their quite different chemicalstructures, enables this composition to function effectively in thevarious intra-cellular compartments occupied by the various agents.

[0101] High levels of AND+ also stimulate other important pathways suchas glycolysis. Up-regulation of glycolysis increases the production ofATP. In addition, AND+ is a feedback inhibitor of phosphoribosyltransferase, the rate-limiting enzyme in the synthesis of AND+, aprocess that consumes ATP. Therefore, increasing the level of AND+results in sparing of ATP and enables cells to better combat anoxidative insult while maintaining redox homeostasis.

[0102] Administration of nicotinamide, an MUT agent, is effective formaintaining appropriate neuronal AND+ levels. In addition,supplementation with nicotinamide augments NADPH, which is associatedwith maintenance of intracellular glutathione levels, decreased DNAfragmentation, and preservation of ATP, as well as preservation of nervecell structure and function.

[0103] Metabolic uncoupling therapy provides useful therapeuticstrategies for treatment of other diseases involving neurodegeneration,such as Huntington's disease and mitochondrial encephalopathy withstroke-like symptoms. MUT is useful for treating neurological disordersincluding various types of traumatic conditions, stroke, hemorrhage,neoplasia, generalized cerebral edema, and iatrogenic damage fromneurosurgical procedures.

EXAMPLE 10

[0104] A specific formulation designed to protect the brain during aneurosurgical procedure was prepared. Typically, a single dose is givenbefore surgery and then repeated every six hours for 72 hours or longerafter the conclusion of the operation. One dose contains: Mannitol 30 gMg-Creatine 5 g ALC 1 g Phosphatidyl choline 2 gGlycerylphosphorylcholine 1 g Choline 250 mg Lipoic acid 1 g Niacinamide1 g Pyridoxine 50 mg Thiamin 100 mg Pantothenic acid 50 mg Pyruvate 5 gGreen Tea Leaf extract 100 mg Vitamin C 500 mg Vitamin E 100 IU CoenzymeQ10 300 mg

[0105] In addition to facilitating the handling of high-energy electronflux via MUT, this formulation addresses other issues, including controlof brain edema, exhaustion of AND+, oxidative stress, hydrogen ionhandling, cerebral energy generation and glucose metabolism. As aresult, the outcome from neurosurgery improves.

[0106] According to the free radical theory of aging, oxidativemetabolism in aerobic cells is accompanied by the reduction of oxygen tosuperoxide radical, hydrogen peroxide and hydroxyl radical. These ROScause damage to cellular components, particularly nuclear andmitochondrial DNA. This leads to impaired function, increased somaticmutations and hence to degeneration and aging. Mitochondria are the mainsource of cellular ROS generation due to an electron leak fromubisemiquinone or other semiquinone moieties in the electron transportchain. Evidence that this ROS production is related to aging includesthe observation that production of ROS is higher in animals with shortermaximal lifespan.

[0107] Cells have powerful anti-oxidant defenses to protect themselvesagainst damage from ROS. The attention in the field has been focused onthese anti-oxidants. On the other hand, regulation of the generation ofROS has been neglected despite the fact that prevention, rather thancure, is a more logical way to ameliorate oxidative damage. Uncouplingagents or increases in ADP reduce ROS production in isolatedmitochondria. ROS production is strongly dependent upon themitochondrial proton motive force (PMF). PMF affects ROS production byaltering the redox state of coenzyme Q. At high PMF, respiration slows.As a result, electrons accumulate on coenzyme Q10, thereby increasingthe concentration of ubisemiquinone, instead of passing down theelectron transport chain to the terminal electron acceptor, oxygen. Thisincreases the instantaneous concentration and half-life ofubisemiquinone, thereby increasing mitochondrial ROS generation.

[0108] Metabolic uncoupling agents in accordance with the inventionlower PMF by limiting the flux of high-energy electrons down the ETC.Various mechanisms accomplish this. This may be achieved in accordancewith the invention by substrate-mediated electron transport betweenmitochondria and cytosol. Substrate-mediated electron transport betweenmitochondria and cytosol is associated with processes that: 1)“discount” the energetic status of these electrons (i.e., NADH ismetabolized to FADH₂ via thealphaglycerophosphate-dihydroxyacetonephosphate shuttle), or 2) engagein futile metabolic pathways that consume ATP, increase ADP and therebycollapse the PMF.

[0109] Without being bound to any particular theory, metabolicuncoupling includes an alternative electron-acceptor substrate thatbinds and neutralizes, or alternatively, transports high-energyelectrons out of the mitochondria. As part of the malate/aspartateshuttle, malate is transported across the mitochondrial membrane inexchange for aspartate. Oxaloacetate (OAA) is generated in mitochondriavia the carboxylation of pyruvate by the enzyme pyruvate carboxylase(PC), or the transamination of aspartate. OAA then acts as the alternateelectron acceptor in a reaction that generates malate. Malate thentransports the electrons into the cytosol across the mitochondrialmembrane (that is otherwise impermeable to electrons). Hence, pyruvateand aspartate, as well as serine or glycine, facilitate the “diversion”of high-energy electrons into the cytosol. In the cytosol, the electronsenter futile ATP-consuming metabolic cycles, or alternatively, theelectrons are transported back into mitochondria in a “discounted”, orlower energy, form as FADH2, as described above. These processes serveto collapse the PMF, with subsequent beneficial effects of decreasingthe generation of ROS.

[0110] Another mechanism in accordance with the invention tending todecrease PMF levels and produce a relative oxidation of coenzyme Q isthe transfer of high-energy electrons to electron acceptors (designatedhere by the letter R) that act as sacrificial molecules, thus generatingan electron sink.

H+R++NADH react to produce AND++RH2

[0111] This mechanism is activated by the use of sacrificial anhydrideacceptors (depicted by the letter R above), rather than oxygen, as theterminal electron acceptors. Examples of such compounds are theredox-active MUT agents included in Groups 1, 3, 5 and 6, as describedin this specification. High doses of single agents pose the risk ofundesirable side-affects. Therefore, in MUT as practiced in accordancewith the invention, combinations of agents comprising specific ratiosand precise amounts, depending on the particular selected mechanisticapproach and on the desired result, are recommended to maximize efficacyand minimize undesirable side effects. Use of a synergistic combinationof multiple agents in relatively small, safe doses formulated inaccordance with the invention circumvents the problem of toxic sideeffects.

[0112] Thus, at least two mechanisms for decreasing ROS levels areprovided by metabolic uncoupling therapy in accordance with theinvention. These mechanisms, either alone or in combination, act“upstream” in the oxidative stress-generating pathway. Prior artsuggests the use of anti-oxidants to quench the damaging ROS presentwithin cells, but it does not address the processes controlling thegeneration of these same ROS. Metabolic uncoupling therapy, as utilizedin accordance with the invention, utilizes a methodology that actsupstream from, and precedes, the generation of these ROS. Thus, similarto other approaches of preventative medicine, MUT safely and effectivelydown-regulates the production of ROS and thereby the aging processitself.

[0113] There are additional synergisms, for example, involving the useof specific agents, such as acetyl L-carnitine (“ALC”), in this holisticapproach. ALC is easily transported into the central nervous system andacts not only as a potent source of anhydride acceptors (carnitine), butalso provides acetyl groups for energy generation and acetylcholinesynthesis. The selection of a MUT agent that achieves a plurality ofdesirable effects (both regarding metabolic uncoupling as well asseparate synergistic effects) is an important feature of embodiments inaccordance with the invention.

[0114] The efficacy of interventions using MUT, which tend to keep ETCsemiquinones in a relatively more oxidized state, parallel resultsachieved from one of the most successful anti-aging interventionsknown—that of caloric restriction. Both caloric restriction and MUTrestrict the supply of high-energy electrons to the oxidized ubiquinonepool. Hence, MUT achieves anti-aging effects via mechanisms similar tothose produced by caloric restriction, but without the necessity ofimposing hunger.

[0115] Inflammation, oxidative stress and nitrogenous stress are keyprocesses in both the intrinsic aging of skin, as well as photo-agingdue primarily to sun exposure. Both intrinsic aging and photo-aginginvolve activation of panels of pro-inflammatory genes byoxidant-sensitive transcription factors, such as AP-1 and nuclear factorkappa B (NFKB). Hydroxyl groups are extremely active, short-lived ROSknown to be generated by ultraviolet radiation (UV). They are importantmodulators of AP-1 and NFKB. As mentioned above, they have a significantreducing potential. Many substances containing reducible groups act asanti-reductants (agents that act to decrease, or diminish, reductivestress). For example, reductive addition of hydroxyl groups to doublebonds of pyrimidines, pyrazines and other aromatic rings may be relatedto the beneficial action of water-soluble vitamins in freeradical-induced stress. Similar reductive reactions are involved in theformation of hydroxy derivatives of nucleic acids, for example, of8-hydroxy-2′-deoxyguanosine, which are incorrectly viewed in the priorart to be principally a result of oxidative stress. An important featureof embodiments in accordance with the invention is application of theconcept that reductive stress, or reductive stress plus the addition ofoxygen, rather than oxidative stress is the driving mechanism behindthis tissue damage.

[0116] In embodiments in accordance with the invention for treatingintrinsic aging and photo-aging, specific combinations, ratios andamounts of MUT agents intervene to protect the vital nucleic acids,proteins and lipids that would otherwise be damaged. Skin-care andanti-aging embodiments in accordance with the invention include topicalapplication of MUT agents. Additionally, certain embodiments utilizeliposomal delivery systems and other absorption enhancers.

EXAMPLE 11

[0117] An exemplary embodiment in accordance with the invention wasformulated for skin care and anti-aging effects using metabolicuncoupling therapy. A liposomal delivery system was optional. Inaddition to the specific metabolic uncoupling properties, additionalproperties of the MUT agents that are functionally synergistic with themetabolic uncoupling functions were reasons for their selection. Theseinclude the fact that lipoic acid is both fat and water-soluble and istherefore readily absorbed transcutaneously. It also has manyanti-inflammatory activities. TMG helps preserve skin barrier function.Phosphatidyl choline facilitates the transport and absorption of many ofthe other ingredients. Coenzyme Q10 is a membrane-active agent. Theexemplary formulation is utilized locally on the appropriate skin areasseveral times per day for an appropriate period of time.

[0118] One 2 oz. Jar contains: R alpha lipoic acid 2 g Coenzyme Q10 1 gTMG 1 g Carnitine 1 g Phosphatidyl choline 3 g Nicotinamide 1 gGlycerylphosphorylcholine 1 g Etidronic acid 600 mg Green tea leafextract 500 mg Vitamin E oil 4 g CLA 4 g Medium chain triglycerides 4 gKojic acid 500 mg Retinyl palmitate 1 g Niacin 500 mg Folate 5 mgPyridoxine 100 mg Glycine 100 mg Arginine 200 mg Aloe vera gel 20 gJojoba oil 24 g

[0119] A formulation also contains de-ionized water, glycerine, glycerylstearate, PEG-100, stearic acid, dimethicone, and methyl paraben.

[0120] Metabolic uncoupling therapy in accordance with the invention isalso useful for avoiding iatrogenic toxicity. Conditions exist in theprior art where proper medical interventions are associated withunavoidable toxicity. Cancer chemotherapy is one such situation. Forexample, Doxorubicin is an anti-proliferative agent that often causescardiomyopathy and nephropathy. This is most likely due to reductivestress related to the dislocation of electrons by the induction of redoxcycling. Anti-reductive MUT diminishes acute toxicity and aids inprolonged survival. ior art lacks similar abilities

EXAMPLE 12

[0121] A formulation was developed for protecting against toxicitysecondary to redox cycling from agents like Doxorubicin. Suggested useis for at least 5 days following administration of the toxic agent,preferably two times to three times a day. Preferably, it isadministered for 24 hours prior to administration of the redox-cyclingagent. Phosphatidyl choline 5 g SAMe 200 mg Myo-inositol 500 mgGlycerylphosphorylcholine 2 g Niacinamide 500 mg Pyruvate 2 g Serine 2 gAlbumin 5 g EPA 2 g GLA (gamma linolenic acid) 600 mg CLA (conjugatedlinoleic acid) 1 g Lipoic acid 300 mg Thiamin 100 mg Folic acid 1 mgL-carnitine 2 g

[0122] Other substances used in medical interventions in the prior artinterrupt the flow of electrons along the electron transport chain.Included in this group are non-steroidal anti-inflammatory drugs(NSAIDs) and cyclosporine. Certain pro-inflammatory cytokines, such asTNFalpha, IL1 and IL6, have similar detrimental effects. These cytokinesare present in infectious, neoplastic or inflammatory conditions, andare also seen status post organ-transplantation. In contrast,embodiments of MUT in accordance with the invention utilize potentanti-reductive capacities of numerous MUT agents combined in specificways in association with their concomitant secondary beneficial actions.These formulations maximize efficacy while minimizing adverse sideeffects.

[0123] Metabolic uncoupling therapy is also useful for enhancingathletic performance and facilitating repair of exercise-relateddysfunction and injury. Various combinations, amounts and ratios of theagents described herein have applicability in numerous pathways relatedto exercise and athletic performance. These may be subdivided generallyinto chronic effects and more acute effects. The former tend to bemediated by chronic modulation of enzyme levels, enzyme activities andgene transcription. The latter involve acute, real time modulation ofvarious metabolic pathways. The artificial acute/chronic division merelyfacilitates descriptive mechanisms, and it is to be noted that there issignificant overlap between the two. Discussion of chronic effects andacute effects serves to enhance understanding of the metabolic pathwaysinvolved and how they are influenced by MUT.

[0124] Modulation of high-energy electron metabolism and pathwaysimpacts numerous mechanisms that influence athletic performance andfunction. Among other benefits and effects, these pathways involvebeneficial modulation of energy generation, expansion of fuel stores,facilitated muscle recovery after exercise, enhanced coupling ofcytosolic and mitochondrial energy-generating pathways, down-regulationof acidosis, improved myoskeletal efficiency, decreased formation ofreactive oxygen species (ROS), down-regulation of inflammatory mediatorsand production of less tissue damage and soreness.

[0125] Ongoing ATP generation is up-regulated by keeping the NADH/AND+ratio in a more oxidized state. This enhances glycolytic as well astricarboxylic acid cycle activity. Enhanced glycolysis occurssimultaneously with a fall in lactate generation and enhanced endogenousgeneration of pyruvate. Acetyl L-carnitine (ALC), carnitine orpantothenic acid augment free CoA levels. Exogenous administration ofpyruvate directly enhances pyruvate levels. These three effects(increased AND+/NADH, increased CoA, increased pyruvate) stimulate themitochondrial enzyme, pyruvate dehydrogenase (PDH), which facilitatescoupling of glycolysis with tricarboxylic acid cycle activity. As aresult, hydrogen ion concentration falls and pH is normalized. Sincecellular handling of hydrogen ions is costly from an energeticperspective, the enhanced coupling of these two metabolic pathwaysmarkedly improves metabolic efficiency and hence muscular functionaloutput.

[0126] The more-oxidized NADH/AND+ redox couple also down-regulatesNADH-dependant oxidase activity, which markedly decreases production oftoxic ROS. This decreases vital tissue injury, enhances function, andacts to diminish one of the primary causes of delayed-onset musclesoreness (DOMS).

[0127] When utilized after exercise, combinations of MUT agents inaccordance with the invention facilitate muscle recovery. This occurs byseveral processes: decreased ROS production diminishes DOMS; improvedredox profile facilitates replenishment of energy supply; improvedinsulin sensitivity speeds up glycogen repletion and has both anabolicand anti-catabolic effects upon protein synthesis; and resolution oflactate build-up and acidosis is accelerated.

EXAMPLE 13

[0128] An exemplary embodiment emulation in accordance with theinvention facilitates post-workout muscle recovery. Duringhigh-intensity muscular workouts, many events occur that stress thefunctional and anatomic properties of the musculo-skeletal system. Largevolumes of muscular work being performed require the generation of largenumbers of high-energy electrons to fuel the process. In addition,during high-intensity exercise, the rate of muscular work beingperformed frequently exceeds the ability of the blood supply to deliveroxygen. This creates a situation where high-energy electrons are beingrapidly generated at a time when there is insufficient oxygen present toact as the terminal electron acceptor for the high flux of electronspassing down the electron transport chain. This creates a conditionwhich induces reductive stress in the muscle cell. As oxygen againbecomes available, the glut of high-energy electrons is transferrednon-enzymatically to oxygen. This results in the creation of superoxideradicals and many other ROS.

[0129] The deleterious effects of this process are greatly magnified inthe presence of free iron. Under these circumstances of (relative)ischemia/reperfusion, free iron is generated upon the reduction offerric to ferrous iron. When this happens, the ferrous iron is releasedfrom its binding protein and free iron is generated. Free iron thencatalyzes the formation of many more ROS. The end result of theseprocesses is the development of a destructive pro-inflammatory state inthe muscle. This produces muscle damage, impaired performance, musclesoreness, predisposition to injury and a prolonged recovery period. Totreat the development of these numerous conditions effectively, it isimportant to understand the mechanisms responsible for theirdevelopment. These mechanisms cause a mismatch between the generationand the safe metabolism of large numbers of high-energy electrons in theaffected muscles. This results in the formation of a large pool ofhigh-energy electrons that initiates multiple damaging pathways. MUTameliorates the excessive flux of electrons and the damage it produces.Since the forces which generate the reductive stress are of largemagnitude, the exemplary MUT formulation includes relatively high dosesand large numbers of active agents in the composition. Multiple highdoses of most of the Group 1 agents were chosen. The main reasons fornot choosing the other Group 1 agents relate to absorption and ease ofuse. Green tea leaf extract was chosen to bind free iron, as well as forpotent anti-oxidant activity. Choline and carnitine were chosen togetherbecause of the beneficial effect of choline upon carnitine levels.Choline also acts as a precursor for acetylcholine, the neurotransmitterat the musculo-skeletal junction. Phosphatidyl choline augments thesesame processes and in addition facilitates membrane function and repairmechanisms. ALA has additional benefits regarding energy generation,iron metabolism, and glucose metabolism. The B vitamins chosen are usedin high doses. In addition to their metabolic-uncoupling activities,they play important secondary roles in energy generation, stressmodulation, glucose metabolism, and in the many avenues of cross-talknecessary for synergistic interaction. Pyruvate also enhances theactivity of the enzyme PDH, as does carnitine (indirectly via elevationof CoA levels), thus better coupling the production and consumption ofhydrogen ions. This beneficially modulates adverse pH effects. Creatinewas included because of its beneficial modulation of energy state andthe enzyme AMPK.

[0130] An individual post-exercise dose contains: NaCl 331 mg NaHCO₃ 252mg K2HPO₄ 100 mg KHCO₃ 100 mg MgSO₄ 180 mg Mg citrate 1400 mg R alphalipoic acid 25 mg Chromium 100 mcg Green tea leaf extract 50 mg ALC 100mg Phosphatidyl choline 250 mg L-carnitine 25 mg Selenium 100 mcgCholine 100 mg Inositol 500 mg TMG 250 mg Pyruvate 250 mg Creatine 1 gB1 50 mg B2 50 mg B3 100 mg B6 50 mg B12 5 mg Vanadyl sulfate 100 mcgGlucose 30 g Whey protein 1 g BCAA 500 mg (BCAA = branched chain aminoacids) Glutamine 375 mg L-arginine 250 mg Natural orange flavor

EXAMPLE 14

[0131] An exemplary embodiment in accordance with the invention wasformulated as a sports performance drink mix. Similar considerationsapply here as were involved in Example 13 above. Special considerationsfor a drink mix that is to be consumed shortly before, or during, asporting event address issues including rapidity of absorption, gastricemptying, and stomach fullness, and are heavily influenced by energygeneration and transduction concerns, and electrolyte shifts. Theseconsiderations explain some of the differences between the twoformulations. An individual dose contains: NaCl 331 mg NaHCO₃ 300 mgK2HPO₄ 150 mg KHCO₃ 150 mg MgSO₄ 260 mg Mg citrate 300 mg Vitamin C 50mg Chromium 50 mcg Selenium 50 mcg Vanadyl sulfate 60 mcg Pyruvate 150mg Carnitine 25 mg Choline 75 mg Inositol 300 mg TMG 150 mg Alpha lipoicacid 20 mg Glucose 30 g Phosphatidyl choline 200 mg BCAA 150 mgGlutamine 125 mg L-arginine 100 mg Thiamin 10 mg Ribose 25 mg Niacin 25mg Vitamin B6 10 mg Natural cranberry flavor

EXAMPLE 15

[0132] An exemplary embodiment in accordance with the invention wasformulated as a muscle-building powder drink mix. There are overlappingconsiderations involving this example and Examples 13 and 14 above. Herethe focus is upon the building of muscle, not sports performance ormuscle recovery after an exhaustive workout. While similarconsiderations regarding high intensity muscle work as were outlined inExample 13 are relevant, the additional emphasis is upon the building ofmuscle, rather than the inhibition of its breakdown and recovery as werediscussed above.

[0133] Muscle building relates to anabolic and vascular considerationsand related issues. These considerations explain the changes in theGroup 1 agents, amounts and ratios. Anabolic effects suggested theincrease in the amount of creatine, the addition of taurine, theincrease in BCAA, and the larger amount of the anti-catabolic agentglutamine. The inclusion of higher amounts of selenium, chromium, ALAand vanadyl sulfate were included to bolster the anabolic effects of theformulation by the insulin sensitizing action of these agents. Thelarger arginine dose, in conjunction with the actions of the insulinsensitizers, maximizes the blood flow to the involved muscles. This actsas a vascular traffic director by preferentially directing the remainderof the ingredients to the desired muscles. The result of these changesmaximizes the local tissue concentrations of the active agents. Thisserves to magnify the end result while minimizing systemic toxicity.Prior art does not teach the use of this combinatorial approach fordevelopment of maximum synergy. One dose per day is recommended. Asingle dose includes: Creatine 10 g Mg citrate 750 mg ALC 300 mgCarnitine 300 mg Choline 300 mg Sphingomyelin 400 mg Chromium 150 mcgSelenium 150 mcg R alpha lipoic acid 100 mg Vanadyl sulfate 150 mcgPyruvate 500 mg Vitamin B1 50 mg Vitamin B2 50 mg Niacinamide 100 mgPyridoxine 20 mg Folic acid 400 mcg Glutamine 2 g L-arginine 400 mgTaurine 250 mg Pyruvate 500 mg BCAA 500 mg Strawberry flavor

[0134] Metabolic uncoupling therapy in accordance with the invention isuseful for ischemia, ischemia/reperfusion injury and for preservingbiological materials. Conditions of ischemia, hypoxia and/or anoxia areassociated with reductive stress as the prime functional insult. Theprior art taught that depletion of ATP was the primary functionalinsult. ATP depletion occurs because as adequate tissue oxygen tensionis compromised, mitochondrial oxygen levels fall. Oxygen is the terminalelectron acceptor in the respiratory process. In its absence,high-energy electrons (i.e., mitochondrial NADH) build up. Thissubsequently inhibits further generation of ATP and produces a host ofdamaging effects in the cell.

[0135] Upon reperfusion (i.e., after resolution of the occlusive orlow-flow vascular state during which oxygen deprivation occurs, or whena preserved organ is transplanted from a donor to a recipient), thesupply of oxygen is returned to the tissues. The combination of a highNADH/AND+ ratio with high tissue-oxygen levels (associated withreperfusion) generates a proliferation of ROS that play a central rolein causing I/R injury and acute transplantation-associated organ insult.Analysis of the relevant metabolic pathways shows the benefits ofmodulating the NADH/AND+ ratio with specific agents in precise amountsand ratios in accordance with the invention.

[0136] Beneficial actions of these formulations modify effects thatoccur acutely and also modulate more sub acute or chronic processes.Acute effects include, among other things, handling of hydrogen ions,prevention of disconjugation of anaerobic glycolysis and glucoseoxidation, regulation of the nucleotide transporter, calcium metabolicaberrations, mechanisms of Na—Ca exchange and other related metabolicpathways. More chronic processes include production of free radicals,subsequent oxidation of membrane lipids, DNA, RNA, and protein moieties,activation of pro-inflammatory transcription factors and production ofclinical symptoms.

EXAMPLE 16

[0137] An exemplary embodiment in accordance with the invention wasformulated as a biological preservation solution. The basic issue hereinvolves the removal of biologic materials from a donor and subsequentre-implantation into a recipient. During the intervening time, thetissue is without blood supply and is un-oxygenated. This defines asituation of ischemia/reperfusion and, as such, the physiologicarguments outlined above apply. The additional constraints involvingagent choices pertain to safety considerations pertinent at the time thebiologic material is re-implanted.

[0138] Ingredients per liter of solution: Pyruvate 5 g Choline 1 g TMG750 mg Vitamin B1 200 mg ALC 1000 mg Lipoic acid 5 g Carnitine 1,000 mgVitamin B3 1,000 mg Vitamin B5 100 mg NACL 75 mg K₂HPO₄ 300 mg Mgcitrate 1,000 mg NaHCO₃ 150 mg Glucose 20 g Penicillin 500 mg Insulin 20units

[0139] A preferred embodiment may include amiloride or calcium channelblockers in clinically recommended dosages.

[0140] Functional foods in accordance with the invention are formulatedby incorporating MUT agents into food and nutritional products. Forprecise metabolic control of high-energy electron metabolism andhandling, specific combinations of MUT active agents are included inbars, drinks, shakes, cookies, salad dressings and the like and therebyconstitute a new category of functional foods.

[0141] For example, low-fat salad dressings generally include highamounts of refined carbohydrates, which are associated with thedevelopment of insulin resistance, elevation of serum triglyceride (TG)levels, lowered HDL (high density lipoprotein), and the development ofan atherogenic, small, dense LDL (low density lipoprotein) profile.Monounsaturated fat, such as is found in olive oil, has beneficialeffects upon metabolic health in these circumstances and alsofacilitates the absorption of the phytonutrients in the salad. However,it is higher in calories since fat contains 9 calories per gram, whereascarbohydrates contain only 4 calories per gram. The inclusion ofspecific amounts, ratios and types of metabolic uncoupling agents asdescribed herein acts to diminish possible weight gain associated withthese otherwise nutritional products, especially if they are usedliberally.

[0142] Without reference to specific mechanisms, fatty acids aremetabolized to carbon dioxide and water in association with thegeneration of high-energy electrons derived from beta-oxidation and thetricarboxylic acid cycle. For the most part, they exist in the formNADH. As these electrons are passed on to oxygen via the electrontransport chain, ATP is generated. Precursors of OAA (such as the agentsof Group 4) act as electron acceptors. When used as supplements inaccordance with the invention, they facilitate the transfer of electronsfrom NADH to OAA (which is generated, for example, by the provision ofpyruvate or aspartate) with subsequent generation of malate. Malate issubsequently transported to the cytosol. This comprises asubstrate-driven electron shuttle from the mitochondria to the cytosol,bypassing electron transfer to oxygen. Once in the cytosol of thehepatocyte, these reducing equivalents may participate inenergy-consuming thermogenic futile cycles, which allow the oxidation offat and the release of energy as heat. These processes are enhanced byspecific combinations of carnitine, Group 4 agents, biotin,hydroxycitrate and other anti-reductive agents, which function aselectron sinks, facilitating futile metabolic cycles, increasing CoAlevels and inducing elevation of ADP. These combinations, in accordancewith the invention, are designed to augment thermogenic (energy-wasting)activity and caloric expenditure, which burn excess calories andcontribute to weight loss.

EXAMPLE 17

[0143] An exemplary embodiment, in accordance with the invention, wasformulated as a salad dressing mixture. Agent choices were made using amethodology as described above in previous examples. In addition,phosphatidyl choline was included because of its ability to function asan emulsifier. ALC additionally raises CoA levels. L-carnitinefacilitates transport of fat into the cellular furnaces for combustion.The following mixture of ingredients is added to 2 oz. of vinegar andolive oil salad dressing: Phosphatidyl choline 50 mg R alpha lipoic acid3 mg TMG 5 mg Myo-Inositol 10 mg ALC 1 mg CLA 10 mg Pyruvate 50 mgBiotin 600 mcg L-carnitine 10 mg Garcinia cambogia extract 20 mgChromium polynicotinate 10 mcg Niacin 10 mg Pantothenic acid 20 mgRiboflavin 20 mg

[0144] A formulation optionally contains Mag-creatine. Mg-creatine 1 g

[0145] The inclusion of the creatine, in association with the aceticacid in the vinegar, activates the fat burning enzyme AMPK. Thisprovides additional beneficial synergies that promote further fatburning.

EXAMPLE 18

[0146] An exemplary embodiment in accordance with the invention wasformulated as a supplementary additive to a protein bar. The compositionis based upon factors similar to those in Example 17, but also includesthe potential for additional healthy metabolic modulation. Thisspecifically relates to improvements in insulin sensitivity withsubsequent benefits in the constellation of symptoms known as theinsulin resistance syndrome (IRS).

[0147] In addition to the beneficial modulation of fat burning pathways,as seen in prior examples, the protein bar additives were chosen also toimprove IRS symptomatology. This involves up-regulation of theelectron-sink pathways, improvement in insulin sensitivity, andbeneficial vascular effects.

[0148] Creatine was chosen because, in addition to its ability tofacilitate MUT, it lowers homocysteine levels. This is beneficial forthe heart. Biotin lowers hepatic glucose output, which stabilizesglucose levels. This improves carbohydrate metabolism in general. Higherlevels of each Group 1 agent were utilized. Higher ALA doses were usedbecause ALA is a potent insulin sensitizer. The spice cinnamon was addedbecause in addition to being a flavoring agent, it also augments insulinsensitivity. The following ingredients are included in one lowcarbohydrate/high protein bar: Creatine 250 mg Carnitine 20 mgAcetoacetate 100 mg R alpha lipoic acid 10 mg Phosphatidyl choline 200mg ALC 25 mg Inositol 50 mg TMG 50 mg Vitamin B2 5 mg Vitamin B3 5 mgVitamin B5 5 mg Biotin 100 mg Pyruvate 200 mg Whey protein 5 g Raisinpuree 200 mg Honey 50 mg MCT 50 mg Deionized water 5 cc Cinnamon powder10 mg Butter 150 mg

EXAMPLE 19

[0149] Skeletal bone loss is associated with inflammatory processes. Itis believed that the statin category of drugs ameliorates osteoporosisby an anti-inflammatory mechanism. Pro-inflammatory transcriptionfactors AP-1 and NFKB play a role. By limiting reductive stress and itssubsequent effects upon AP-1 and NFKB, MUT acts in a similaranti-inflammatory fashion.

[0150] Prior art has stressed calcium supplementation as the cornerstoneof a successful program for bone health. While calcium deficiency maycertainly be a risk factor for osteopenia, bone disorders are notnecessarily cured by supplemental calcium.

[0151] Examination of evolutionary nutrition and its effects upon bonemetabolism helps explain issues of bone health. Neanderthal nutritionalmodeling studies arrive at similar conclusions to those of directstudies of modern day hunter-gather cultures consuming their nativediets. When interpreted from the perspective of dietary intake and itseffect upon nutritional acid load to the body, great differences arenoted between our “ancestral” diet and current dietary intake. Modernfood choices expose us to a large acid load, day after day, throughoutour lifetimes. In comparison, our evolutionarily based diet delivered aneutral, or even slightly alkaline, load. This contrasts starkly withmodern cuisine. This situation is at nutritional odds with our geneticlegacy and-metabolic impacts.

[0152] The effect of chronic acid loading is to lower the pH of theblood. The pH in blood is metabolically regulated in a healthyindividual and is kept within a narrow range. This is necessary becauseof the severe consequences of even minor pH changes. The appropriatebodily response to an acid load is to buffer the pH change. Thisbuffering effect tends to restore pH to the normal range. This is abeneficial physiologic action and forms the basis for regulation of thepH in blood.

[0153] There is, however, a dark side to this process if it continuesfor an extended period of time. This is easily understood if theprocesses responsible for this buffering are investigated. The largestpool of acid buffer in the body is its carbonate reservoir. This residesalmost exclusively in our bone mass where it is anchored by the mineralmatrix. Calcium is one of these binding agents. As carbonate leaves thebone matrix, on its way to the blood stream where the pH bufferingoccurs, calcium is an unwilling participant in the same journey. Thisprocess, the simultaneous loss of bone calcium and carbonate, over timeinduces a slow, gradual progressive loss of bone mass and manifestsitself as osteoporosis.

[0154] The calcium that leaves the bone reservoir makes its way to theblood stream. Just as blood pH is carefully regulated, so is the bloodcalcium level. To prevent any significant rise in the blood calciumlevel, renal compensatory mechanisms are activated. These involve theloss of calcium in the urine. In this manner, the majority of thecalcium lost from bone ends up in the urine. From this perspective it iseasy to see why calcium supplementation is not the treatment of choicefor osteoporosis. At best, it might only prevent calcium deficiency fromdeveloping. Indeed, many individuals on high dose calciumsupplementation protocols develop calcium stones in their urinary tract.

[0155] Chronic nutritional metabolic acidosis may be viewed as anirritant to the body, much like infection or inflammation. The mostlogical treatment for osteoporosis is nutritional. Inappropriate dietarychoices cause the calcium loss, so appropriate dietary choices mayprevent the calcium loss. As explained above, this does not includehigh-dose calcium supplementation.

[0156] When for any reason appropriate dietary choices are impractical,then a backup plan that otherwise addresses the causative mechanism isindicated. This includes the use of dietary supplements that correct thediet-induced metabolic acidosis and its deleterious effects upon bone.Included in a preferred formulation is a potassium salt having an anionthat is either bicarbonate or a metabolic precursor, such as citrate.Potassium bicarbonate (KHCO₃) may be taken easily, is well tolerated andimmediately corrects the metabolic acidosis. This obviates the need forcarbonate from bone to act as a buffer and physiologically remedies theproblem of acidosis related bone loss.

[0157] A more complete program includes an MUT formulation to treat theinflammatory component of the disorder. Such a composition includes acombination of MUT agents already discussed in combination withpotassium bicarbonate or citrate. Calcium and/or vitamin D or an analogare optionally included. The chosen agents should be well toleratedorally, complement calcium metabolism, have a good safety profile, andbe active in bone tissue. Such a composition is listed below. A dailydose (which may be taken in divided doses) includes: KHCO₃ 6 g Serine100 mg Alpha lipoic acid 100 mg B6 50 mg B12 1 mg Folate 1 mg Choline250 mg Carnitine 300 mg TMG 500 mg ALC 300 mg

[0158] It optionally includes: Vitamin D 400 IU Calcium (chelate) 1000mg

[0159] This combination is applicable in numerous food productsincluding, but not limited to, milk or milk products, juices, shakes,salad dressing, gravies, sauces, nutritional bars, protein powders, andany other palatable food products.

[0160] Embodiments in accordance with the invention have been describedherein mainly with reference to human physiology and metabolism. Theinvention is generally useful and widely applicable in mammalianphysiology and veterinary medicine. Examples of useful applicationsinclude enhancement of athletic performance in greyhounds or racehorses,enhanced and prolonged fertility in breeding stock, and healthmaintenance in household pets.

[0161] It should be understood that the specific formulations andmethods described herein are exemplary and should not be construed tolimit the invention, which will be described in the claims below.Further, it is evident that those skilled in the art may now makenumerous uses and modifications of the specific embodiments described,without departing from the inventive concepts. Also, the inventioncontemplates that formulations in accordance with the invention may bemade of many other combinations of MUT agents than those described aboveand claimed below. There are many other variations of clinical andmetabolic situations, specific methods of addressing such situations,and MUT formulations and compositions than can be included in a documentsuch as this. Consequently, the invention is to be construed asembracing each and every novel feature and novel combination of featurespresent in and/or possessed by the compositions and methods describedand by their equivalents.

1. A composition of agents for metabolic uncoupling therapy, comprising:two or more Group 1 agents; one or more Group 4 agents; two or moreGroup 5 agents; and one or more Group 6 agents; wherein Group 1 agentsare selected from a group consisting of TMG (Trimethylglycine), choline,phosphatidyl choline, SAMe (S-adenosyl methionine), carnitine, ALC(acetyl L-carnitine), propionyl carnitine, (myo)inositol, sphingomyelin,glycerylphosphorylcholine, and acetylcholine; Group 4 agents areselected from a group consisting of PYR (Pyruvate), ASP (Aspartate), GLY(Glycine), and SER(Serine); Group 5 agents are selected from a groupconsisting of Folate, riboflavin, B1, B3, niacinamide, nicotinamide,polynicotinate, B6, B12, biotin, pantothenic acid, riboflavin, andrelated chemical species; and Group 6 agents are selected from a groupconsisting of coenzyme Q10, lipoic acid, and acetoacetate:
 2. Acomposition as in claim 1, further comprising: a Group 2 agent, selectedfrom a group consisting of creatine and folic acid.
 3. A composition asin claim 2 comprising creatine and TMG, wherein a weight ratiocreatine/TMG has a value in a range of about from 1/20 to 30/1.
 4. Acomposition as in claim 2 comprising creatine and carnitine, wherein aweight ratio creatine/carnitine has a value in a range of about from1/10 to 250/1.
 5. A composition as in claim 2 comprising creatine andpyruvate, wherein a weight ratio creatine/pyruvate has a value in arange of about from 1/20 to 25/1.
 6. A composition as in claim 2comprising creatine and aspartate, wherein a weight ratiocreatine/aspartate has a value in a range of about from 1/10 to 25/1. 7.A composition as in claim 1, further comprising: a Group 3 agent,selected from a group consisting of DHA (Docosahexanoic acid), EPA(Eicosapentanoic acid), and albumin.
 8. A composition as in claim 1,further comprising: a Group 7 agent, selected from a group consisting ofpolyphenolic agents and desferoximine.
 9. A composition as in claim 1,comprising: coenzyme Q10, R alpha lipoic acid, TMG, phosphatidylcholine, SAMe, carnitine and aspartic acid.
 10. A composition as inclaim 1, comprising: creatine, R alpha lipoic acid, SAMe, EPA, TMG,pyruvate, phosphatidyl choline, and ALC.
 11. A composition as in claim1, comprising: aspartate, biotin, HCA, chromium, carnitine, choline,TMG, SAMe, ALA, folic acid, creatine, and niacinamide.
 12. A compositionas in claim 11, further comprising MCT.
 13. A composition as in claim 1,comprising: tocotrienols, aspartic acid, biotin, HCA, TMG, inositol,guggulipid, and folic acid.
 14. A composition as in claim 13, furthercomprising CLA.
 15. A composition as in claim 1, comprising: coenzymeQ10, ALA, EPA, chromium, aspartate, biotin, folate, L-arginine andcreatine.
 16. A composition as in claim 1, comprising: phosphatidylcholine, choline, lysine, glutamine, ALA, niacin, folic acid, pyridoxalphosphate, SAMe, ALC, CLA, and EPA.
 17. A composition as in claim 1,comprising: glycerylphosphorylcholine, creatine, ALC, ALA, niacinamide,coenzyme Q10, phosphatidyl choline, choline, and TMG.
 18. A compositionas in claim 1, comprising: sodium chloride, potassium, magnesium,glucose, ALA, ALC, Mg-creatine chelate, huperzine A, pyridoxalphosphate, folate and vitamin B12.
 19. A composition as in claim 1,comprising: niacinamide, ALC, inositol, folic acid, choline,phosphatidylcholine, and ALA.
 20. A composition as in claim 1,comprising: mannitol, Mg-creatine, ALC, phosphatidyl choline,glycerylphosphorylcholine, ALA, thiamin, pyridoxine, coenzyme Q10 andniacinamide.
 21. A composition as in claim 1, comprising: ALA, coenzymeQ10, TMG, phosphatidyl choline, niacinamide, vitamin C and vitamin E.22. A composition as in claim 1, comprising: ALA, coenzyme Q10, TMG,phosphatidyl choline, and CLA.
 23. A composition as in claim 1,comprising: phosphatidylcholine, glycerylphosphorylcholine, pyruvate,serine, albumin, EPA, CLA, and ALC.
 24. A composition as in claim 1,comprising: NaCl, ALA, green tea leaf extract, ALC, phosphatidylcholine,carnitine, L-arginine, magnesium citrate, choline, pyruvate, creatineand vitamin B12.
 25. A composition as in claim 1, comprising: NaCl,pyruvate, carnitine, choline, inositol, TMG, ALA, phosphatidylcholine,BCAA, glutamine, ribose and vitamin B6.
 26. A composition as in claim 1,comprising: creatine, taurine, BCAA, glutamine, ALC, carnitine, choline,sphyngomyelin, chromium, selenium, ALA, vanadyl sulfate, and arginine.27. A composition as in claim 1, comprising: pyruvate, choline, TMG,ALC, NaHCO₃, carnitine, pantothenate, vitamin B3, magnesium citrate,insulin, and antibiotic.
 28. A composition as in claim 1, comprising:phosphatidyl choline, ALA, ALC, pyruvate, hydroxycitrate, biotin,chromium and carnitine.
 29. A composition as in claim 28, furthercomprising: magnesium creatine.
 30. A composition as in claim 1,comprising: whey protein, niacin (B3), folate, creatine, carnitine,acetoacetate, ALA, phosphatidylcholine, ALC, inositol, TMG, biotin, andpyruvate.
 31. A composition as in claim 1, comprising: potassiumbicarbonate, serine, ALA, choline, carnitine, TMG, and ALC.
 32. Acomposition as in claim 31 further comprising vitamin D and calcium. 33.A composition as in claim 1, comprising three or more Group 1 agents.34. A composition as in claim 33, comprising three or more Group 5agents.
 35. A composition as in claim 1, comprising four or more Group 1agents.
 36. A composition as in claim 35, comprising three or more Group5 agents.
 37. A method of metabolic uncoupling therapy comprising:analyzing a specific physiologic process, including delineating themetabolic pathways related to reductive stress; identifying a pluralityof MUT agents that modulate said metabolic pathways by influencingelectron flux; and formulating a combination of MUT agents that limitsthe accumulation of high-energy electrons potentially available to theelectron transport chain.
 38. A method of metabolic uncoupling therapyas in claim 37 comprising: including an MUT agent in said combinationbased on said agent's secondary properties.
 39. A method as in claim 37,further comprising: selecting a plurality of MUT agents based on theirsynergistic interactions with each other.
 40. A method as in claim 37,further comprising: combining specific amounts and ratios of saidplurality of MUT agents in a MUT formulation for administration in aprescribed manner for a prescribed period of time.